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Obesity is a strong risk factor for nephrolithiasis, but the role of physical activity and caloric intake remains poorly understood. We evaluated this relationship in 84,225 women with no history of stones as part of the Women's Health Initiative Observational Study, a longitudinal, prospective cohort of postmenopausal women enrolled from 1993 to 1998 with 8 years' median follow-up. The independent association of physical activity (metabolic equivalents [METs]/wk), calibrated dietary energy intake, and body mass index (BMI) with incident kidney stone development was evaluated after adjustment for nephrolithiasis risk factors. Activity intensity was evaluated in stratified analyses. Compared with the risk in inactive women, the risk of incident stones decreased by 16% in women with the lowest physical activity level (adjusted hazard ratio [aHR], 0.84; 95% confidence interval [95% CI], 0.74 to 0.97). As activity increased, the risk of incident stones continued to decline until plateauing at a decrease of approximately 31% for activity levels ≥10 METs/wk (aHR, 0.69; 95% CI, 0.60 to 0.79). Intensity of activity was not associated with stone formation. As dietary energy intake increased, the risk of incident stones increased by up to 42% (aHR, 1.42; 95% CI, 1.02 to 1.98). However, intake <1800 kcal/d did not protect against stone formation. Higher BMI category was associated with increased risk of incident stones. In summary, physical activity may reduce the risk of incident kidney stones in postmenopausal women independent of caloric intake and BMI, primarily because of the amount of activity rather than exercise intensity. Higher caloric intake further increases the risk of incident stones.